Cadherin-mediated adhesion is a vital morphogenetic process that results in the formation of highly organized intercellular junctions. For the past decade, our laboratory has been studying the molecular details that underlie the process. Our experiments suggest that cadeherin-mediated adhesion is based on the continuous formation of short-lived cadherin adhesive dimers. One of the notable features of these dimers is their stability: once extracted from cells, the dimers are stable in SDS concentrations as high as 0.2%. Calcium is required for their formation, but not for their maintenance. They appear to be organized according to the strand dimer model, which is one of numerous biophysical models for cadherin dimers. Both the formation and disassembly of the dimers are complex and cell-regulated processes. Their disassembly is mediated, at least in part, by cadherin endocytosis. These two processes-cadherin dimer assembly and disassembly-are proposed to control the strength and plasticity of cell-cell contacts. Cadherin adhesive dimers-specifically, their functional significance and the molecular principles of their assembly-are the main subjects of Specific Aim 1. In addition, site-specific cross-linking analysis will be used to define the diversity of cadherin-cadherin interactions in both adherens junctions and desmosomes. The intracellular processes regulating the clustering and lifetime of adhesive dimers are central subjects of Specific Aim 2. This Aim will also study whether adhesive dimerization induces any changes in the interactions between the cadherin and catenins (proteins that associate with the intracellular region of cadherin). The work designed is critical to understanding the molecular basics of many cell-cell adhesion diseases- tumor cell invasiveness and metastasis, in particular. This work is also a critical step toward the development of synthetic adhesion modulators and their application in medicine.